The delivery of drugs through the skin provides many advantages; primarily, such a means of delivery is a comfortable, convenient and noninvasive way of administering drugs. The variable rates of absorption and metabolism encountered in oral treatment are avoided, and other inherent inconveniences--e.g., gastrointestinal irritation and the like--are eliminated as well. Transdermal drug delivery also makes possible a high degree of control over blood concentrations of any particular drug.
Skin is a structurally complex, relatively thick membrane. Molecules moving from the environment into and through intact skin must first penetrate the stratum corneum and any material on its surface. They must then penetrate the viable epidermis, the papillary dermis, and the capillary walls into the blood stream or lymph channels. To be so absorbed, molecules must overcome a different resistance to penetration in each type of tissue. Transport across the skin membrane is thus a complex phenomenon. However, it is the cells of the stratum corneum which present the primary barrier to absorption of topical compositions or transdermally administered drugs. The stratum corneum is a thin layer of dense, highly keratinized cells approximately 10-15 microns thick over most of the body. It is believed to be the high degree of keratinization within these cells as well as their dense packing which creates in most cases a substantially impermeable barrier to drug penetration.
In order to increase skin permeability, and in particular to increase the permeability of the stratum corneum (i.e., so as to achieve enhanced penetration, through the skin, of the drug to be administered transdermally), the skin may be pretreated with a penetration enhancing agent (or "permeation enhancer", as sometimes referred to herein) prior to application of a drug; alternatively, a drug and a permeation enhancer are concurrently delivered.
The rate at which transdermal drug delivery occurs can be expressed as skin flux, i.e., as a quantity of drug which passes through a unit of skin surface area per unit time. Skin flux is affected by several factors, one of which is skin permeability.
Another factor which affects skin flux is the solubility of the drug in the reservoir in which it is contained. In certain kinds of transdermal systems, where the drug is only poorly soluble in the reservoir, skin flux varies over time; that is, while initially drug flux is well above the minimum value required to obtain pharmaceutically effective levels of the drug, flux subsequently declines to a point below the target value.
This effect is especially problematic in cases where steady state delivery of a drug over an extended time period is desired. A method for overcoming this problem, and obtaining a steady-state flux profile, is to solubilize a higher percentage of the drug in the reservoir. Doing so reduces the initial flux rate, and consequently increases the flux at later times, owing to the higher concentration of dissolved drug remaining in the reservoir; the net result is improved steady state delivery.
The present invention is directed to a novel method and composition for enhancing the solubilization of a drug in the drug reservoir in which it is contained. The invention is premised on the discovery that adding certain acidic agents to the drug reservoir enhances the solubility of the drug in the reservoir and thus improves steady state delivery of the drug.